Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors.
The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT(4)) receptors in pheochromocytoma tissues. Tissue explants, obtained from 18 pheochromocytomas including the tumor removed from a 46-year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant) were studied. Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT(4) receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine- and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays. In addition, expression of 5-HT(4) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR.


RESULTS
Metoclopramide and the 5-HT(4) receptor agonist cisapride were found to activate catecholamine- and granin-derived peptide secretions by cultured tumor cells. Metoclopramide- and cisapride-evoked catecholamine- and granin-derived peptide productions were inhibited by the 5-HT(4) receptor antagonist GR 113808. 5-HT(4) receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT(4) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine- and granin-derived peptide secretion. All 5-HT(4) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma.
Guillemot
Johann
J
INSERM U413, University of Rouen, Mont Saint Aignan, France.
Compagnon
Patricia
P
Cartier
Dorthe
D
Thouennon
Erwan
E
Bastard
Christian
C
Lihrmann
Isabelle
I
Pichon
Perrine
P
Thuillez
Christian
C
Plouin
Pierre-François
PF
Bertherat
Jérôme
J
Anouar
Youssef
Y
Kuhn
Jean-Marc
JM
Yon
Laurent
L
Lefebvre
Hervé
H
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002864:Chromogranins / Q000378:metabolism; D020117:Cisapride / Q000494:pharmacology; D000075202:Contraindications; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008787:Metoclopramide / Q000494:pharmacology*; D008875:Middle Aged; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002395:Catecholamines; D002864:Chromogranins; D018492:Dopamine Antagonists; D012333:RNA, Messenger; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D004294:Domperidone; D008787:Metoclopramide; D020117:Cisapride